Randomized Phase 2 Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease

Abstract

Objective:To determine whether locally acting ACE-083 is safe, well tolerated, and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1.Methods:This phase 2 study enrolled adults with CMT1 or CMTX (N=63). Part 1 was open-label and evaluated safety and tolerability of different dose levels of ACE-083 for use in Part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally in the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-meter walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests.Results:In Part 1 (n=18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious AEs, TEAEs ≥Grade 3, or death reported. In Part 2 (n=45 enrolled, n=44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (LS mean difference: 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate-to-mild injection-site reactions were the most common TEAEs.Conclusions:Despite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo.Classification of evidence:This study provides Class II evidence that intramuscular ACE-083 is safe, well tolerated, and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.

AAV-mediated editing of PMP22 rescues Charcot-Marie-Tooth disease type 1A features in patient-derived iPS Schwann cells

“…However, these findings have not been confirmed in clinical trials. Meanwhile, clinical trials including ascorbic acid 58 , 59 (NCT00484510), a myostatin inhibitor 60 and progesterone receptor antagonist (NCT02600286) have failed to identify clinical benefits for CMT1A patients.…”

The Current State of Charcot–Marie–Tooth Disease Treatment

“…The study comprised 62 patients diagnosed with CMT1 and CMTX1. Unfortunately, the program was prematurely terminated before advancing to phase III due to disappointing results; despite an observed increase in muscle volume, this physiological change failed to yield significant enhancements in practical or quality-of-life procedures when related with the placebo (NCT03124459) [27].…”

The Current State of Charcot–Marie–Tooth Disease Treatment

“…The study comprised 62 patients diagnosed with CMT1 and CMTX1. Unfortunately, the program was prematurely terminated before advancing to phase III due to disappointing results; despite an observed increase in muscle volume, this physiological change failed to yield significant enhancements in practical or quality-of-life procedures when related with the placebo (NCT03124459) [37].…”